Anions modulate the potency of geranylgeranyl-protein transferase I inhibitors.

We have identified and characterized potent and specific inhibitors of geranylgeranyl-protein transferase type I (GGPTase I), as well as dual inhibitors of GGPTase I and farnesyl-protein transferase. Many of these inhibitors require the presence of phosphate anions for maximum activity against GGPTase I in vitro. Inhibitors with a strong anion dependence were competitive with geranylgeranyl pyrophosphate (GGPP), rather than with the peptide substrate, which had served as the original template for inhibitor design.

HIV-1 integrase inhibitors that compete with the target DNA substrate define a unique strand transfer conformation for integrase.

Diketo acids such as L-731,988 are potent inhibitors of HIV-1 integrase that inhibit integration and viral replication in cells. These compounds exhibit the unique ability to inhibit the strand transfer activity of integrase in the absence of an effect on 3' end processing. To understand the reasons for this distinct inhibitory profile, we developed a scintillation proximity assay that permits analysis of radiolabeled inhibitor binding and integrase function.

Cyclodiene insecticide resistance: from molecular to population genetics.

This review follows progress in the analysis of cyclodiene insecticide resistance from the initial isolation of the mutant, through cloning of the resistance gene, to an examination of the distribution of resistance alleles in natural populations. Emphasis is given to the use of a resistant Drosophila mutant as an entry point to cloning the associated gamma-aminobutyric acid (GABA) receptor subunit gene, Resistance to dieldrin. Resistance is associated with replacements of a single amino acid (alanine302) in the chloride ion channel pore of the protein.

Ascites syndrome and related pathologies in feed restricted broilers raised in a hypobaric chamber.

It has been demonstrated that the incidence of ascites can be significantly reduced through feed restriction. This method is thought to have an effect by slowing the growth rate of the birds. Interestingly, when birds are grown in a hypobaric chamber, ascites incidence increases while the overall growth rate of the birds is decreased.

Effect of feed withdrawal or challenge with Pasteurella multocida on growth, blood metabolites, circulating growth hormone, and insulin-like growth factor-I concentrations in eight-week-old turkeys.

The daily effects of feed withdrawal or a bacterial disease (Pasteurella multocida; PM) challenge was studied in a slow-growing line of turkeys. The following groups (n = 6 birds/group) were sampled for up to 13 d: untreated control (CON), 4-d feed withdrawal followed by refeeding (FAST), a group that succumbed within the first 2 to 3 d after PM challenge (E-DEAD), a group that succumbed 8 to 9 d after PM challenge (L-DEAD), a group that survived the PM challenge (SUR), and a group treated with both PM challenge and 4-d feed withdrawal followed by refeeding (FAST/CHAL). Daily feed intake and BW gains were markedly reduced in the E-DEAD and L-DEAD groups immediately and 3 d after PM challenge, respectively.

Design and in vivo analysis of potent non-thiol inhibitors of farnesyl protein transferase.

Inhibitors of farnesyl protein transferase (FPTase) based upon a pseudotripeptide template are described that comprise an imidazole group substituted with a hydrophobic substituent. (1, 5)-Disubstitution of the imidazole group is shown to be the optimal array that leads to potent and selective inhibitors of FPTase. A variety of aryl and isoprenyl substituents are shown to afford effective inhibitors, and the mechanism by which these compounds inhibit FPTase has been investigated.

Electrocardiographic evaluation of broilers following unilateral occlusion of an extrapulmonary primary bronchus.

This study was conducted to provide a comprehensive evaluation of both the amplitudes and durations of the Lead II electrocardiogram (ECG) in nonascitic and ascitic broilers. At 14 d of age, male and female broiler chicks were sham-operated (SHAM, n = 27), or pulmonary hypertension was initiated by occluding one extrapulmonary primary bronchus (BRONCHUS CLAMP, n = 57). Lead II ECG and BW were recorded on Days 28 (ECG1) and 42 (ECG2), necropsies were conducted on all birds dying after Day 28, and final necropsies were conducted on Day 49.

Electrocardiographic and genetic evaluation of giant jungle fowl, broilers, and their reciprocal crosses following unilateral bronchus occlusion.

Electrocardiography is useful as a noninvasive technique for detecting right ventricular hypertrophy in birds developing pulmonary hypertension (PH) and pulmonary hypertension syndrome (PHS, ascites). The objective of this study was to identify every aspect of the Lead II ECG wave form (amplitude or duration) that can be correlated with right ventricular hypertrophy [increased right:total ventricular weight ratios (RV:TV)] indicative of PH across a broad genetic background. Sham operations were conducted, or PH was induced by occluding one extrapulmonary primary bronchus in 14-d-old chicks produced from matings of broilers (B x B), Giant Jungle Fowl (J x J), and their reciprocal crosses (B x J and J x B).

Why are there so few resistance-associated mutations in insecticide target genes?

The genes encoding the three major targets of conventional insecticides are: Rdl, which encodes a gamma-aminobutyric acid receptor subunit (RDL); para, which encodes a voltage-gated sodium channel (PARA); and Ace, which encodes insect acetylcholinesterase (AChE). Interestingly, despite the complexity of the encoded receptors or enzymes, very few amino acid residues are replaced in different resistant insects: one within RDL, two within PARA and three or more within AChE. Here we examine the possible reasons underlying this extreme conservation by looking at the aspects of receptor and/or enzyme function that may constrain replacements to such a limited number of residues.

Duplication of the Rdl GABA receptor subunit gene in an insecticide-resistant aphid, Myzus persicae.

Resistance to cyclodiene insecticides is associated with replacements of a single amino acid (alanine 302) in a gamma-aminobutyric acid (GABA) receptor subunit encoded by the single-copy gene Resistance to dieldrin (Rdl). Alanine 302 is predicted to reside within the second membrane-spanning region of the Rdl receptor, a region that is thought to line the integral chloride ion channel pore. In all cyclodiene-resistant insects studied to date, this same alanine residue is replaced either by a serine, or, in some resistant strains of Drosophila simulans, a glycine residue.

Flow-dependent pulmonary vasodilation during acute unilateral pulmonary artery occlusion in Jungle Fowl.

Giant Jungle Fowl previously were shown to be highly resistant to the onset of pulmonary hypertension syndrome (PHS, ascites) under conditions that induce a substantial incidence of PHS in broiler chickens. In the present study, lightly anesthetized, clinically healthy 12- to 13-wk-old male Giant Jungle Fowl maintained a lower respiratory rate, a similar hematocrit, and superior arterial blood gas values when compared with 6-wk-old male broilers. Giant Jungle Fowl weighed less than broilers (1,860 +/- 19 vs 2,788 +/- 63 g, respectively) and had equivalent absolute values for pulmonary arterial pressure, cardiac output, and pulmonary vascular resistance.

Effects of amino acid restriction during starter and grower periods on subsequent performance and incidence of leg disorders in two strains of male large white turkeys.

Male turkeys of two commercial Large White strains (Nicholas 88, BUT 6) were subjected to growth restriction by means of reducing amino acid (AA) content of diets to a minimum of 75% of NRC (1994) suggested levels. There were three periods when diets containing 75% of NRC recommended AA for that age period were fed ad libitum: 0 to 3 wk, 0 to 6 wk, or 6 to 12 wk. A fourth (control) group was not restricted in AA content at any time.

Analysis of a mosquito acetylcholinesterase gene promoter.

Insect acetylcholinesterase is the target site for organophosphorus and carbamate insecticides and point mutations in the Ace gene are associated with resistance in Drosophila melanogaster and Musca domestica. However, little is known of the genetic regulation of insect Ace genes. Here we report the isolation of four different cDNAs from an Aedes Ace locus and identification of the gene promoter.

Molecular mapping of insecticide resistance genes in the yellow fever mosquito (Aedes aegypti).

Several loci conferring insecticide resistance in the yellow fever mosquito (Aedes aegypti) have previously been mapped by simple recombinational mapping. Here we describe correlation of these resistance phenotypes with molecular gene probes for insecticide target sites by RFLP mapping. The para sodium channel gene homologue and the GABA receptor gene Resistance to dieldrin map to the same genome regions as the DDT/pyrethroid and cyclodiene resistance loci, respectively.

Ornithine decarboxylase activity in muscle, liver, and intestinal tissue of turkeys during a short-term feed withdrawal and following refeeding.

The activity of ornithine decarboxylase (ODC), an enzyme associated with cellular growth and protein synthesis, was examined in breast muscle, liver, and intestinal tissues of turkeys during a short-term period of feed withdrawal (FW) and following refeeding. Turkeys from a randombred control line were reared under standard management practices to 3 wk of age in battery brooders. Feed was then withdrawn from FW birds for a 48-h period, after which feed was consumed ad libitum.

Response of two strains of large white male turkeys to amino acid levels when diets are changed at three- or four-week intervals.

A study was conducted to evaluate the amino acid recommendations of the NRC (1994) when diets were changed at 3- or 4-wk intervals. Diets formulated to provide from 90 to 115% of recommended amino acid levels were fed to Nicholas (NIC) and British United Turkey (BUT) Large White males from day-old to 24 wk of age; samples of turkeys were processed at 18 and 24 wk. Results indicated that the amino acid levels suggested by NRC are adequate to support maximum body weight gain, feed conversion, and dressing percentage of Large White males grown to 18 or 24 wk when fed on 4-wk intervals.

Dietary interactions between lysine and threonine in broilers.

Two experiments were conducted to evaluate the effects of two dietary levels of lysine and four dietary levels of threonine in a factorial arrangement on broiler growth, carcass traits, and immunity. In both experiments, 120 broilers were allocated to each of 56 floor pens (6,720 total broilers). In Experiment 1, two levels of lysine (1.

Divergent selection for body weight and yolk precursor in Coturnix coturnix japonica. 12. Heterosis in reciprocal crosses between divergently selected lines.

A selection experiment was started using Japanese quail to study the genetics of BW and plasma yolk precursor (measured by total plasma phosphorus; TPP). Lines were divergently selected for 4-wk BW (HW and LW) or plasma TPP (HP and LP). Sublines of HW were developed by continuing to select the males for increased 4-wk BW while selecting the females for increased (HW-HP line) or decreased (HW-LP line) TPP.

Effect of the genetic selection of turkeys for increased body weight and egg production on immune and physiological responses.

Selection of poultry for fast growth rate is often accompanied by a reduction in specific immune responses or increased disease susceptibility. In this study, 17-wk-old male turkeys from each of four closed genetic lines, a randombred control (RBC) line and its subline (F) selected for increased 16-wk BW, and another RBC and its subline (E) selected for increased egg production, were tested for in vivo response to toe web inoculation with phytohemagglutinin-P (PHA-P), in vitro response of lymphocytes in whole blood to PHA-P and concanavalin A (Con A), hemolytic complement activity, differential white blood cell counts, hematology, and serum chemistry values. Fifteen male turkeys from each of two commercial lines, Com A and Com B, were also tested.

Nucleic acid concentrations and ornithine decarboxylase activity in tissues from three lines of turkeys.

Developmental patterns in turkeys of tissue ornithine decarboxylase (ODC) activity and nucleic acid concentrations were studied in a randombred control (RBC2), in a subline of RBC2 selected for increased 16-wk BW (F), and in a commercial sire line (C). Lines F and C were similar in BW, but Line C had greater breast weight than Line F. Lines F and C were heavier and had greater breast weights than the RBC2 population.

Farnesyl: proteintransferase inhibitors as agents to inhibit tumor growth.

Ras, a signal-transducing protein involved in mediating growth factor-stimulated proliferation, is mutationally activated in over 30% of human tumors. To be functional Ras must bind to the inner surface of the plasma membrane, with post-translational lipid modifications being necessary for this localization. The essential, first modification of Ras is farnesylation catalyzed by the enzyme farnesyl: proteintransferase (FPTase).

Effect of intermittent activity on broiler production parameters.

The use of intermittent lighting in broiler production has been shown to result in spurts of activity that appear to reduce lameness. Because intermittent lighting is difficult to achieve in curtain-sided houses, the objective of this study was to determine whether simple equipment used to increase activity in broilers would improve production variables. At 1 d of age, 840 male broiler chicks were placed in 24 floor pens.

Short-term selection for four-week body weight in Japanese quail.

Japanese quail have been utilized as a research animal to establish genetic relationships that may be present in other poultry species. In this presentation, short-term selection experiments were reviewed. Selection intensity appeared to be the most effective in improving BW when selection experiments were compared on a response per generation basis; however, when generation interval was reduced, the response per year was superior despite lower selection intensities for lines selected the same number of generations.

Divergent selection for body weight and yolk precursor in Coturnix coturnix japonica. 11. Correlated responses over thirty generations.

Japanese quail lines were divergently selected for 4-wk BW (HW and LW lines) and plasma yolk precursor [total plasma phosphorus (TPP); HP and LP lines] for 30 generations. The base population was a randombred control line (R1) that was maintained along with the selected lines. Sublines were established from the ninth selected generation of HW by continuing to select males for increased 4-wk BW and selecting females for increased (HW-HP line) or decreased (HW-LP line) TPP.